Neurodegenerative and
psychiatric disorders including Alzheimer's, Parkinson's or Huntington's diseases and
schizophrenia have been associated with a deficit in
glutathione (GSH). In particular, a polymorphism in the gene of
glutamate cysteine ligase modulatory subunit (GCLM) is associated with
schizophrenia. GSH is the most important intracellular
antioxidant and is necessary for the removal of reactive by-products generated by the utilization of
glucose for energy supply. Furthermore,
glucose metabolism through the pentose phosphate pathway is a major source of
NADPH, the cofactor necessary for the regeneration of
reduced glutathione. This study aims at investigating
glucose metabolism in cultured astrocytes from GCLM knockout mice, which show decreased GSH levels. No difference in the basal metabolism of
glucose was observed between wild-type and knockout cells. In contrast,
glycogen levels were lower and its turnover was higher in knockout astrocytes. These changes were accompanied by a decrease in the expression of the genes involved in its synthesis and degradation, including the
protein targeting to
glycogen. During an oxidative challenge induced by
tert-Butylhydroperoxide, wild-type cells increased their
glycogen mobilization and
glucose uptake. However, knockout astrocytes were unable to mobilize
glycogen following the same stress and they could increase their
glucose utilization only following a major oxidative insult. Altogether, these results show that
glucose metabolism and
glycogen utilization are dysregulated in astrocytes showing a chronic deficit in GSH, suggesting that alterations of a fundamental aspect of brain energy metabolism is caused by GSH deficit and may therefore be relevant to metabolic dysfunctions observed in
schizophrenia.